Preparation of 1-oxapenicillins and 4-acyloxy azetidinone intermediates therefor

ABSTRACT

The invention provides a novel process for opening the ring of 2-R-6-(1&#39;-R 1  -oxycarbonyl-2&#39;-methyl-prop-1&#39;-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-en-7-one by treatment with a sulfonic acid salt thereby forming R 1  2-(2&#39;R-R-oxy-3&#39;S-amino-4&#39;-oxo)azetidinyl-3-methyl-2-butenoate sulfonic acid salts which can provide oxapenicillins by two different routes depending on the substituent desired on the carboxamido group of the 1-oxapenicillins. In the alternate processes, new intermediates are also provided.

This is a division of application Ser. No. 587,571, filed June 17, 1975,now U.S. Pat. No. 4,071,512, which was co-pending of application Ser.No. 496,620 filed Aug. 12, 1974, now U.S. Pat. No. 3,948,972 which inturn was a continuation of U.S. Ser. No. 242,842 filed Apr. 10, 1972.

The present invention relates to novel intermediates which areparticularly useful in the preparation of 1-oxapenicillins and to anovel process for obtaining said novel intermediates.

PRIOR ART

The cyclization of a2-(2'-R-mercapto-3'-acylamino-4'-oxo)azetidinyl-3-methyl-2-butenoic acidto a penicillin has been reported by S. Wolfe et al., J. Amer. Chem.Soc., Vol. 91, 1969, p. 7205. ##STR1##

The formation of the thiazolidine ring proceeds by the Michael reactionas described in ORGANIC REACTIONS, Vol. 10 p. 179, and in RussianChemical Reviews, Vol. 38, 1969, p. 884.

For the preparation of various 1-oxapenicillins of the general formula:##STR2## wherein R⁰ is an acyl radical, it would be useful to have aprocedure for the preparation of a2-(2'R-hydroxy-3'S-acylamino-4'-oxo)azetidinyl-3-methyl-2-butenoic acid(the hydroxyl analog of the above-mentioned mercaptan), because thecyclization of this compound by the Michael reaction will generate thedesired oxazolidine ring.

A potentially useful intermediate for the preparation of such a2-(2'R-hydroxy-3'S-acylamino-4'-oxo)azetidinyl-3-methyl-2-butenoic acidis an oxazoline of the formula: ##STR3## wherein R⁰ and R¹ both standfor an organic radical. Such oxazolines have the correct oxidationlevel, functionality and absolute configurations at the 4- and5-positions. Hydrolytic opening of the five-membered ring at the 1-2bond would generate the desired alcohols but no simple procedure existsto effect the ring opening in this way. In some recent work by Corbetand Stoodley, J. Chem. Soc. Perkin I, 1974, p. 185, it is the 1-5 bondwhich breaks. In Canadian Pat. No. 1,024,518 issued Jan. 17, 1978, filedMar. 22, 1973, corresponding to U.S. Pat. application Ser. No. 242,842,filed Apr. 10, 1972, now U.S. Pat. Nos. 3,948,927, 3,950,352, 3,985,764S. Wolfe, inventor, the oxazolines have been converted directly intooxapenicillins by a procedure which requires rigorously anhydrousexperimental conditions.

The oxazolines I (R⁰ ═PhCH₂, PhOCH₂) are available directly frompenicillin G or penicillin V by the methods of J. C. Sheehan, "MolecularModification in Drug Design," Advances in Chemistry Series No. 45,American Chemical Society, Washington, D. C., 1964, p. 15; D. H. R.Barton et al, J. Chem. Soc. (C), 1971, p. 3540; and Stoodley andWhitehouse, J. Chem. Soc. Perkin I, 1974, p. 181. A general synthesis ofoxazolines I from2-(2'R-chloro-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoic acid isdescribed in Canadian Pat. No. 1,024,518 issued Jan. 17, 1978 filed Mar.22, 1973 corresponding to U.S. Pat. application Ser. No. 242,842, filedApr. 10, 1972, now U.S. Pat Nos. 3,948,927, 3,950352, 3,985,764.

THE INVENTION

In accordance with the present invention there is now provided a methodto open the ring of oxazolines of the general formula: ##STR4## wherein

R stands for loweralkyl ##STR5## wherein

Ar is a monovalent radical selected from ##STR6## wherein R₁, R₂ and R₃are each a member selected from hydrogen, chloro, bromo, iodo,trifluoromethyl, phenyl, loweralkyl and loweralkoxy, but only one ofsaid R₁, R₂ and R₃ may represent phenyl;

R⁴ is hydrogen, amino, carbobenzoxyamino, phenyl, fluoro, chloro, bromo,iodo, hydroxy, loweralkanoyloxy and loweralkoxy;

X is oxygen or sulfur;

R⁵ and R⁶ are hydrogen, phenyl, benzyl, phenethyl and loweralkyl;

Z¹, Z² and Z³ stand for loweralkyl or the Ar- group;

R¹² is 2,2,2-trichloroethyl or benzyl; and

R¹ is loweralkyl, benzyl, benzhydryl, loweralkoxybenzyl, or2,2,2-trichloroethyl.

Preferred values for R are loweralkyl, such as methyl or pentyl,phenoxymethyl, thienylmethyl and allylmercaptomethyl and preferredvalues for R¹ are methyl, benzyl, benzhydryl, methoxymethyl and allreadily removable groups as will be hereinafter defined.

In accordance with the present invention, the ring in the oxazoline I,which is the 2-R-6-(1'R¹-oxycarbonyl-2'-methyl-prop-1'-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-en-7-one(I) may be readily opened to form the novel azetidinone sulfonic acidsalt (II) by treatment with the monohydrate of a sulfonic acid. The ringopening may be illustrated as follows: ##STR7## wherein A is the residueof a sulfonic acid.

As monohydrate of a sulfonic acid there may be used p-toluenesulfonicacid or benzenesulfonic acid or other sulfonic acids having anequivalent acidity.

The novel azetidinones II provide the advantage that they can then bereadily converted to various 1-oxapenicillins in accordance with thefollowing Flowsheet I: ##STR8##

As can be readily appreciated from the above reaction sequence the novelintermediates (II) of the present invention are useful to prepare1-oxapenicillin by two different routes depending on whether it isdesired to have the value of R in the 1-oxapenicillin the same as in thestarting oxazoline I or different than in the oxazolline I.

1Oxapenicillin by Route A.

This route is conveniently used when it is desired that the value of Rbe the same in the 1-oxapenicillin as in the starting oxazoline I. Inthis sequence the sulfonic acid salt II is first neutralized to allowfor rearrangement of the RCO-substituent from the 2'-position to the3'-position. The neutralization step is carried out at room temperatureor below in an aqueous organic solvent such as acetone, tetrahydrofuran,dimethylsulfoxide, N,N-dimethylformamide and the like or in a two phasesystem containing water and an immiscible organic solvent such asmethylene chloride, chloroform, ether, benzene, ethyl acetate and thelike over a period of at least thirty minutes thus forming theazetidinone IIA. Neutralization is carried out with any of the usualinorganic or organic bases. As an example of suitable inorganic basesthere may be mentioned alkali metal carbonates or bicarbonates such assodium or potassium carbonate or bicarbonate, and lithium carbonate;alkali metal hydroxides such as sodium or potassium hydroxides; alkalineearth carbonates such as strontium or calcium carbonate, and organicnitrogeneous bases such as the usual secondary or tertiary amines knownto be useful as neutralizing agents such as diethylamine, triethylamine,diazabicyclononene or diazabicycloundecene. Preferably, whenneutralizing with a strong base no more than one molar equivalent ofsuch a base should be used. It should be appreciated that the criticalfeature of this step is that the reaction mixture should be allowed tostand until the RCO-group in the 2'-position of compound II hastransferred to the 3'-position of compound IIA. Thus, for example in themixture of water and chloroform containing 2 molar equivalents oftriethylamine, the time required to transfer the RCO-group from the2'-position to the 3'-position is at least 11/2 hours when carrying outthe reaction at room temperature.

Cyclization of the azetidinone IIA is carried out conveniently by theMichael addition procedure described by S. Wolfe in J.A.C.S. Vol. 91, p.7205, 1969.

1-Oxapenicillin by Route B.

This route is conveniently used when it is desired to prepare a1-oxapenicillin wherein the R group is different from the one present inthe starting oxazoline I. For example, there may be situations where itis not feasible to have a certain substituent for R in the oxazoline Ibut these same substituents might be desirable in the 1-oxapenicillin.

As a first step, the sulfonic acid salt II is neutralized in anhomogeneous or heterogeneous system and in the presence of an acidchloride of the formula R"COCl to form the azetidinone IIB.

As acylating agents there may be used an organic monocarboxylic acidchloride of the formula: ##STR9##

wherein R⁴ represents a member selected from the group consisting ofhydrogen, amino, carbobenzoxyamino, phenyl, fluoro, chloro, bromo, iodo,hydroxy, (lower)alkanoyloxy and (lower)-alkoxy; X represents a memberselected from the group consisting of oxygen and sulfur; R⁵ and R⁶ eachrepresent a member selected from the group consisting of hydrogen,phenyl, benzyl, phenethyl and (lower)alkyl; R⁷ represents (lower)alkyl;R⁸ and R⁹ each represent a member selected from the group consisting of(lower)alkyl, (lower)alkylthio, benzylthio, cyclohexyl, cyclopentyl,cycloheptyl, benzyl, phenethyl, phenylpropyl, furyl, thienyl, naphthyland Ar-; R¹⁰ represents a member selected from the group consisting of(lower)alkylamino, di(lower)alkylamino, cycloalkylamino having from 3 to7 carbon atoms inclusive, allylamino, diallylamino,phenyl(lower)alkylamino, morpholino, (lower)alkylmorpholino,di(lower)alkylmorpholino, morpholino(lower)alkylamino, pyrrolidino,(lower)alkylpyrrolidino, di(lower)alkylpyrrolidino,N,N-hexamethyleneimino, piperidino, (lower)alkylpiperidino,di(lower)-alkylpiperidino, 1,2,5,6-tetrahydropyridino,N-(lower)-alkylpiperazino, N-phenylpiperazino,N-(lower)alkyl(lower)-alkylpiperazino,N-(lower)alkyl-di(lower)alkylpiperazino, furfurylamino,tetrahydrofurfurylamino, N-(lower)alkyl-N-furfurylamino,N-alkyl-N-anilino and (lower)alkoxyanilino; Z¹, Z² and Z³ each representa member selected from the group consisting of (lower)alkyl and Ar-; R¹¹represents a member selected from the group consisting of (lower)alkyl,(lower)-cycloalkyl, naphthyl, benzyl, phenethyl and ##STR10## and Ar-represents a monovalent radical having one of the formulae: ##STR11##wherein R¹³, R² and R³ are each a member selected from the groupconsisting of hydrogen, chloro, bromo, iodo, trifluoromethyl, phenyl,(lower)alkyl and (lower)alkoxy, but only one R group may representphenyl; or with a functional equivalent of said acid chloride.

The term "(lower)alkyl" as used herein means both straight and branchedchain aliphatic hydrocrbon radicals having from one to ten carbon atomssuch as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl,amyl, hexyl, 2-ethylhexyl, heptyl, decyl, etc. Similarly, where thisterm "(lower)" is used as part of the description of another group, e.g."(lower)alkoxy," it refers to the alkyl portion of such group which istherefore as described above in connection with "(lower)alkyl."

The functional equivalents of the above acid chlorides as an acylatingagent for a primary amino group include the corresponding carboxylicacid bromides, acid anhydrides, including mixed anhydrides andparticularly the mixed anhydrides prepared from stronger acids such asthe lower aliphatic monoesters of carbonic acid of alkyl and arylsulfonic acids and of more hindered acids such as diphenylacetic acid.In addition, an acid azide or an active ester or thioester (e.g. withp-nitrophenol, 2,4-dinitrophenol, thiophenol, thioacetic acid) may beused or the free acid itself may be coupled with the primary amine afterfirst reacting said free acid with N,N'-dimethylchloroforminium chloride[cf. Great Britain 1,008,170 and Novak and Weichet, Experientia XXI/6,360 (1965) ] or by the use of enzymes or of an N,N'-carbonyldiimidazoleor an N,N'-carbonylditriazole [cf. South African Patent Specification63/2684], of a carbodiimide reagent [especiallyN,N'-dicychlohexylcarbodiimide, N,N'-diisopropylcarbodiimide orN-cyclohexyl-N'-(2-morpholinoethyl)-carbodiimide; cf. Sheehan and Hess.J. Amer. Chem. Soc. 77, 1067, (1955)], or of alkynylamine reagent; [cf.R. Buijle and H. G. Viehe, Angew. Chem. International Edition 3, 582(1964) ], or of a ketenimine reagent [cf. C. L. Stevens and M. E. Monk,J. Amer. Chem. Soc. 80, 4065 (1-58)] or of an isoxazolium salt reagent[cf. R. B. Woodward, R. A. Olofson and H. Mayer, J. Amer. Chem. Soc. 83,1010 (1961)]. Another equivalent of the acid chloride is a correspondingazolide, i.e. an amide of the corresponding acid whose amide nitrogen isa member of a quasiaromatic five-membered ring containing at least twonitrogen atoms, i.e. imidazole, pyrazole, the triazoles, benzimidazole,benzotriazole and their substituted derivatives. As an example of thegeneral method for the preparation of an azolide,N,N'-carbonyldiimidazole is reacted with a carboxylic acid in equimolarproportions at room temperature in tetrahydrofuran, chloroform,dimethylformamide or a similar inert solvent to form the carboxylic acidimidazolide in practically quantitative yield with liberation of carbondioxide and one mole of imidazole. Dicarboxylic acids yielddiimidazolides. The byproduct, imidazole, precipitates and may beseparated and the imidazolide isolated but this is not essential. Themethods for carrying out these reactions to produce a penicillin and themethods used to isolate the pencillins so-produced are well-known in theart.

Saponification of the azetidinone IIB will provide the azetidinone IIC.This step may be carried out using condition similar to those employedfor the transformation of the sulfonic acid salt (II) to the azetidinoneIIA.

Finally the azetidinone IIC is converted to the 1-oxapenicillin (IIIA)in the same manner as described in Route A.

The 1-oxapenicillin derivatives III and IIIA may readily be converted tothe corresponding free acids by any of the known methods for convertingesters to free acids.

An additional feature of the present invention is that the azetidinonesII obtained herein can also be used to prepare novel bromo derivativesof 1-oxapenicillin XXVI corresponding to the following general formula:##STR12## wherein R and R¹ are as previously defined.

These novel bromo deriviates of 1-oxapencillin XXVI may be prepared inaccordance with the Flowsheet II: ##STR13##

The novel bromo 1-oxapenicillins XXVI are prepared by first brominatingthe sulfonic acid salts II with at least one molar equivalent ofN-bromosuccinimide in refluxing carbon tetrachloride or methylenechloride containing a catalytic amount of benzoyl peroxide in thepresence of light thereby to form a mixture of the sulfonic acid saltsXX and XXI.

This mixture of the azetidinones XX and XXI is then neutralized to allowrearrangement of the RCO-substituent from the 2'-position to the3'-position. This neutralization step is carried out at room temperatureor below in an aqueous organic solvent such as acetone, tetrahydrofuran,dimethylsulfoxide, N,N-dimethylformamide and the like or in a two phasesystem containing water and an immiscible organic solvent such asmethylene chloride, chloroform, ether, benzene, ethyl acetate and thelike to form the mixture of azetidinones XXII and XXIII. Neutralizationis carried out with any of the usual inorganic or organic bases. As anexample of suitable inorganic bases there may be mentioned alkali metalcarbonates or bicarbonates such as sodium or potassium carbonate orbicarbonate, and lithium carbonate; alkali metal hydroxides such assodium or potassium hydroxides; alkaline earth carbonates such asstrontium or calcium carbonate, and organic nitrogeneous bases such asthe usual secondary or tertiary amines known to be useful asneutralizing agents such as diethylamine, triethylamine,diazabicyclononene or diazabicycloundecene. Preferably when neutralizingwith a strong base no more than one molar equivalent of such a baseshould be used.

Finally, the mixture of azetidinones XXII and XXIII may then eithercyclize by the Michael addition procedure described in J.A.C.S. Vol. 91,p, 7205, 1969 to provide the novel brominated oxapenicillins XXVI, orundergo further rearrangement to the novel oxazinone derivatives XXV. ;

EXAMPLE 1 Reaction of2-benzyl-6-(1'-methoxycarbonyl-2'-methyl-prop-1'-enyl-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-en-7-onewith p-toluenesulfonic acid-monohydrate ##STR14##

The2-benzyl-6-(1'-methoxycarbonyl-2'-methyl-prop-1'-enyl-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-en-7-one(500 mg, 1.6 mMoles) and p-toluenesulfonic acid monohydrate (300 mg, 1.6mMoles) were stirred in dry acetone (20 ml) for 30 min. The solvent wasthen removed below 40° to give a colorless foam which was crystallizedfrom acetonehexane to give 480 mg (60%) of methyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate as colorless fine needles, after washing with coldethyl acetate, m.p. 145°-146°, [α]_(D) ^(EtOH) 40.1 (c 0.17).

Anal. Calcd. for C₂₄ H₂₈ N₂ O₈ S: C, 57.14; H, 5.56. Found: C, 56.75; H,5.85.

The NMR spectrum has peaks at 7.83 (2H, d, 9 Hz), 7.06 (5H, s), 7.06(2H, d, 9 Hz), 6.30 (1H, d, 4.0 Hz;), 4.90 (1H, d, 4.0 Hz), 3.62 (3H,s), 3.52 ;(2H, s), 2.30 (3H, s), 2.03 (3H, s), 1.88 (3H, s).

In KBr, the IR spectrum has peaks at 1800, 1776, 1728, 1699 cm⁻¹.

Proceeding in the same manner and replacing p-toluenesulfonic acidhydrate by benzenesulfonic acid hydrate there is obtained thecorresponding benzenesulfonic acid salt having a m.p. 134° C.-135° C.

EXAMPLE 2

Proceeding in the same manner as above, but substituting for the2-benzyl-6-(1'-methoxycarbonyl-2'-methylprop-1'-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-ene-7-one,the corresponding 2-phenoxymethyl, the 2-n-pentyl, the2-(2-thienylmethyl), the 2-(3-thienylmethyl), and the2-allyl-mercaptomethyl compounds, there are obtained the followingsalts:

1. methyl2-(2'-R-phenoxyacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

2. methyl2-(2'R-caproyloxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

3. methyl2-[2'R-(2-thienylacetoxy)-3'S-amino-4'-oxo-]azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

4. methyl2-[2'R-(3-thienylacetoxy)-3'S-amino-4'-oxo]-azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

5. methyl2-(2'R-allylthioacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate.

The reactions just named are: ##STR15##

EXAMPLE 3 Reaction of2-benzyl-6-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-ene-7-onewith p-toluenesulfonic acid monohydrate ##STR16## Step A:

The2-benzyl-6-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-ene-7-one(1.1 g, 2.8 mMoles) and p-toluenesulfonic acid monohydrate (532 mg, 2.8mMoles) and p-toluenesulfonic acid monohydrate (532 mg, 2.8 mMoles) werestirred in dry acetone (50 ml) for 30 min. Removal of the solventafforded a quantitative yield of benzyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate, m.p. 128°-130° dec., after crystallization fromethyl acetate-petroleum ether.

The NMR spectrum has peaks at 7.68 (2H, d, 8 Hz), 7.15 (5H, s), 6.97(5H, s), 6.93 (2H, d, 8 Hz), 6.23 (1H, d, 4Hz), 5.02 (s, 2H), 4.73 (brd, 4 Hz), 3.43 (2H, s), 2.23 (3H, s), 1.97 (3H, s), 1.50 (3H, s).

Step B:

The benzyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate (100 mg) was hydrogenated at 15 psi in absoluteethanol (20 ml) containing 5% palladium on charcoal (10 mg) to give2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoicacid p-toluenesulfonate, having the structure: ##STR17##

The NMR spectrum has peaks at 7.67 (2H, d, 8 Hz), 7.17 (5H, s), 7.00(2H, d, 8 Hz), 6.35 (1H, d, 4 Hz), 4.97 (1H, d, 4 Hz), 3.47 (2H, s),2.23 (3H, s), 2.00 (3H, s), 1.58 (3H, s).

EXAMPLE 4

Proceeding in the same manner as in Step A of Example 3, butsubstituting for the2-benzyl-6-(1'-benzyloxycarbonyl-2'-methylprop-1'-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-en-7-one,the corresponding 2-phenoxymethyl, the 2-n-pentyl, the2-(2-thienylmethyl), the 2-(3-thienylmethyl), and the2-allylmercaptomethyl compounds, there are obtained the following salts:

1. benzyl2-(2'R-phenoxyacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

2. benzyl2-(2'R-caproyloxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

3. benzyl2-[2'R-(2-thienylacetoxy)-3'S-amino-4'-oxo]-azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

4. benzyl2-[2'R-(3-thienylacetoxy)-3'S-amino-4'-oxo]-azetidinyl-3-methyl-2-butenoatep-toluenesulfonate;

5. benzyl2-(2'R-allylthioacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate.

The reactions just named are: ##STR18##

EXAMPLE 5

In the same manner as Step B of Example 3, benzyl2-(2'R-phenoxyacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate affords2-(2'R-phenoxyacetoxy-3'S-amino-4'-oxo(azetidinyl-3-methyl-2-butenoicacid p-toluenesulfonate;

benzyl2-(2'R-caproyloxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate affords2-(2'R-caproyloxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoic acidp-toluene-sulfonate;

benzyl2-[2'R-(2-thienylacetoxy)-3'S-amino-4'-oxo]azetidinyl-3-methyl-2-butenoatep-toluenesulfonate affords2-[2'R-(2-thienylacetoxy)-3'S-amino-4'-oxo]azetidinyl-3-methyl-2-butenoicacid p-toluenesulfonate;

benzyl2-[2'R-(3-thienylacetoxy)-3'S-amino-4'-oxo]azetidinyl-3-methyl-2-butenoatep-toluenesulfonate affords2-[2'R-(3-thienylacetoxy)-3'S-amino-4'-oxo]azetidinyl-3-methyl-2-butenoicacid p-toluenesulfonate;

benzyl2-(2'-R-allylthioacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate affords2-(2'R-allylthioacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoicacid p-toluenesulfonate.

EXAMPLE 6 Conversion of Azetidinones II to Azetidinones IIB ##STR19##

The benzyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)-azetidinyl-3-methyl-2-butenoatep-toluenesulfonate obtained in Example 1 (500 mg, 1.0 mMole) in CH₂ Cl₂(40 ml), cooled to 0°, was shaken vigorously for 30 min in an ice-bathwith an ice cold solution of sodium bicarbonate (263 mg, 3.0 mMoles) inwater (20 ml). Then a solution of benzoyl chloride (280 mg, 2.0 mMoles)in CH₂ Cl₁ (10 ml) was added dropwise during 5 min and stirringcontinued at 0° for an additional 2 hr. The layers were then separtedand the aqueous layer extracted twice with CH₂ Cl₂. Evaporation of thecombined dried CH₂ Cl₂ layers afforded 550 mg of a colorless solid.Recrystallization from CH₂ Cl₂ -petroleum ether gave 330 mg (75.5%) ofmethyl 2-(2'R-phenylacetoxy-3'S-benzoylamino-4'-oxo)azetidinyl-3-methyl-2-butenoate (R═C₆ H₅) as colorless prisms, m.p. 139°-141°.

The IR spectrum (KBr) has peaks at 1777, 1722, 1669 cm⁻¹.

The NMR spectrum has peaks at 7.78-6.97 (6H, m), 7.13 (5H, s), 6.37 (1H,d, 4 Hz), 5.58 (1H, 9, 2, 8 Hz), 3.73 (3H, s), 3.57 (2H, s), 2.18 (3H,s), 1.83 (3H, s).

To prove the structure of this compound,2-benzyl-6-(1'-methoxycarbonyl-2'-methylprop-1'-enyl)-1-oxa-3,6-diaza-4S,5R-bicyclo[3,2,0]hept-2-en-7-one(the methyl ester of the oxazoline) was converted directly into the samematerial. The oxazoline (100 mg, 0.3 mMole) and benzoyl chloride (140mg, 1 mMole) were stirred in THF (5 ml) at room temperature for 24 hr.Then water (2 ml) and NaHCO₃ (100 mg, 1.2 mMole) were added, andstirring continued for a further 30 min. The mixture was then dilutedwith water and extracted with CH₂ Cl₂. After drying of this extract,evaporation yielded 140 mg of a yellow oil, whose NMR spectrum showed itto be a mixture of oxazoline and the above-mentioned N-benzoyl compound.This latter material was isolated by p.l.c. on silica gel (elution with1:2 ethyl acetate:hexane) and crystallized from ethyl acetate-hexane.Its IR, NMR spectra, m.p. and mixture melting point with the N-benzoylcompound showed the two to be identical.

The meaning of this experiment is that benzoylation of the oxazolinemust occur on nitrogen (E. M. Fry, J. Org. Chem., 15, 802 (1950)). Inthe formation of the diacylated azetidinone from the salt no O→N acyltransfer has, therefore, occurred.

In a second experiment, the salt was converted into the N-phenylacetylcompound by exactly the same procedure, except that acylation of thefree amine was performed with phenylacetyl chloride. The structure ofthis latter compound is ##STR20## This compound has IR absorption at2.9, 3.0, 5.60, 5.70, 5.80, 5.98, 6.05, 6.65μ. The NMR spectrum haspeaks at 2.65-2.75 (10H, m), 3.26 (1H, d, 9.5 Hz), 3.68 (1H, d, 4.1 Hz),4.53 (q, 4.1, 9.5 Hz), 6.27 (3H), 6.43 (2H), 6.54 (2H), 7.82 (3H), 8.28(3H). The mass spectrum shows a molecular ion at m/e 450.

EXAMPLE 7 Acylation of Azetidinones II to Azetidinones IIB ##STR21##

By proceeding in the same manner as in Example 6 and replacing thebenzoyl chloride with α-aminophenylacetyl chloride,α-hydroxyphenylacetyl chloride, tetrazyl-1-yl-acetyl chloride,thiophen-2-yl-acetyl chloride, (3-phenyl-5-methylisoxazol-4-yl)acetylchloride or α-carboxy-phenylacetyl chloride there is obtained thecorresponding methyl2-(2'R-phenylacetoxy-3'S-α-aminophenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoate,methyl2-(2'R-phenylacetoxy-α-hydroxyphenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoate,methyl2-(2'R-phenylacetoxy-3'S-tetrazyl-1-yl-acetamido-4'-oxo)-azetidinyl-3-methyl-2-butenoate,methyl2-(2'R-phenylacetoxy-3'S-thiophen-2-yl-acetamido-4'-oxo)azetidinyl-3-methyl-2-butenoate,methyl2-(2'R-phenylacetoxy-3'S-[3-phenyl-5-methylisoxazol-4-yl]acetamido-4'-oxo)azetidinyl-3-methyl-2-butenoateand methyl2-(2'R-phenylacetoxy-3'S-α-carboxyphenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoatewhich upon treatment in accordance with the following Examples willyield the 6-D(α)-aminophenylacetamido-oxapenicillanic acid,6-D(α)hydroxyphenylacetamido-oxapenicillanic acid,6-tetrazyl-1-yl-acetamidooxapenicillanic acid,6-thiophen-2-yl-acetamido-oxapenicillanic acid,6-[3-phenyl-5-methylisoxazol-4-yl]acetamidooxapenicillanic acid, and6[D](α)carboxy-phenylacetamidooxapenicillanic acid.

EXAMPLE 8 Conversion of2-(2'R-phenylacetoxy-3'S-phenylacetamido-4'-oxo)-azetidinyl-3-methyl-2-butenoicacid to2,2-dimethyl-3R-carboxy-6S-phenylacetamido-1-oxa-4-aza-5R-bicyclo[3,2,0]heptan-7-onevia2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoicacid ##STR22##

Forty-five milligrams of2-(2'R-phenylacetoxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoicacid are dissolved in ice-cold 0.05N methanolic sodium methoxide (4 ml).The solution containing the2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoicacid is stirred at 0°for 2 hr, and is then neutralized with ice-colddilute HCl and extracted with ether. Evaporation of the dried etherextract yields 30 mg of material, which is found to contain phenylaceticacid and2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)-azetidinyl-3-methyl-2-butenoicacid. This material is dissolved in water (0.5 ml) containing sodiumbicarbonate (42 mg) and after 3 hr, a 5 μl aliquot is allowed toevaporate upon a 1 cm-diameter filter paper. This is introduced onto anagar plate seeded with S. lutea, and the plate is allowed to developovernight at 37°. A zone of inhibition, attributed to the presence ofoxapenicillin G, is then observed. (cf. S. Wolfe et al, J. Amer. Chem.Soc., 91, 7205 (1969)).

EXAMPLE 9 Conversion of Methyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)-azetidinyl-3-methyl-2-butenoatep-toluenesulfonate to Methyl2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoateand Cyclization to the Methyl Ester of Oxapenicillin G ##STR23##

A solution of Methyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate (II) in CDCl₃ is treated with two molar-equivalentsof triethylamine, and the IR spectrum of the resulting solution ismonitored as a function of time. After 2 min, the spectrum of methyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoateshows peaks at 5.60, 5.65 and 5.78μ, corresponding to the β-lactam, thephenylacetoxy and the carbomethoxy carbonyl groups. During the next 1.5hr, the β-lactam absorption remains, but the phenylacetoxy absorption at5.65μdisappears and phenylacetamido absorption appears at 5.98μ,corresponding to the O→N acyl transfer which forms the methyl2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-2-butenoate.

Alternatively, the p-toluenesulfonic acid salt (II) (47 mg, 0.093 mMole)is dissolved in DMSO-d₆ (1 ml), TMS is added, and the NMR spectrum isrecorded. This spectrum shows the 3'-proton as a doublet (4 Hz) at 5.08,the 4'-proton as a doublet (4 Hz) at 6.38, the CH₂ protons at 3.74, themethyl ester protons at 3.67, the methyl protons of thep-toluene-sulfonate ion at 2.28, and the gem-dimethyl protons at 2.10and 1.82. A solution of K₂ CO₃ (6.4 mg. 0.047 mMole) in D₂ O (0.2 ml) isnow added, and the NMR spectrum of the resulting solution is secured atintervals during a period of 26 hr. The 3'-proton becomes a quartet(J=4, 12 Hz) at 6.27, the 4'-proton becomes a doublet (J=4 Hz) at 5.00,the CH₂ protons shift upfield to 3.60, and the gem-dimethyl protonsshift upfield to 2.00 and 1.72. The reaction mixture is then dilutedwith water and extracted with chloroform. The dried chloroform extractis concentrated and its IR spectrum recorded. This shows OH and NHabsorption at 2.90 and 2.94μβ-lactam absorption at 5.60μ, conjugatedester at 5.81μ, and amide absorption at 6.02μ, corresponding to theformation of the compound methyl2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)-azetidinyl-3-methyl-2-butenoate.

This compound is cyclized to the methyl ester of 1-oxapenicillin G bythe procedure of Example 8.

EXAMPLE 10 Removal of the phenylacetyl group from methyl2-(2'R-phenylacetoxy-3'S-benzoylamino-4'-oxo)azetidinyl-3-methyl-2-butenoate##STR24##

The methyl2-(2'R-phenylacetoxy-3'S-benzoylamino-4'-oxo)azetidinyl-3-methyl-2-butenoate(100 mg) is dissolved in absolute ethanol (1 ml) containing pyridine(0.5 ml). This solution is cooled to 0° and then an additional 0.5 ml ofethanol is added, followed by 2N sodium hydroxide (0.5 ml). The mixtureis stirred at 0° for 5 min, and is then acidified with ice-cold diluteHCl. Extraction with methylene chloride and evaporation of the driedorganic layer affords phenylacetic acid and methyl2-(2'R-hydroxy-3'S-benzoylamino-4'-oxo)azetidinyl-3-methyl-2-butenoate.

This compound is then cyclized to2,2-dimethyl-3R-methoxycarbonyl-6S-benzoylamino-1-oxa-4-aza-5R-bicyclo[3,2,0]-heptan-7-oneby the procedure of Example 8.

EXAMPLE 11 Conversion of methyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)-azetidinyl-3-methyl-2-butenoatep-toluenesulfonate to2-isopropenyl-2-methoxycarbonyl-5-phenylacetamido-5,6-dehydrooxazine-4-oneand the epimeric2-bromomethyl-2-methyl-3R-methoxycarbonyl-6S-phenylacetamido-1-oxa-4-aza-5R-bicyclo[3,2,0]heptan-7-ones##STR25##

The methyl3-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-2-butenoatep-toluenesulfonate (504 mg, 1 mMole) was brominated for 15 min in CCl₄(50 ml) with N-bromosuccinimide (356 mg, 2 mMoles to yield a mixture ofthe methyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)azetidinyl-3-methyl-trans-2-butenoatep-toluenesulfonate XX and corresponding cis-4-bromo isomer XXI. Thismixture was dissolved in CH₂ Cl₂ (30 ml) containing triethylamine (202mg. 2 mMoles) to form the mixture of methyl2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-trans-4-bromo-2-butanoateand methyl2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-cis-4-bromo-2-butenoateand this solution was stirred at room temperature for 1 hr and thenevaporated to dryness. The residue was triturated with methylenechloride and water and the dried methylene chloride phase was evaporatedto give 310 mg of a white foam. Crystalline material m.p. 151°-152° C.was obtained as follows. The crude product was chromatographed on silicagel and eluted with 1:1 petroleum ether:ethyl acetate. Crystallizationfrom petroleum ether-CH₂ Cl₂ afforded 210 mg of the2-isopropenyl-2-methoxycarbonyl-5-phenylacetamido-5,6-dehydrooxazine-4-one.Calcd. for C₁₇ H₁₈ N₂ O₅ (M+1) 330.1205. Found: 330.1216.

The NMR spectrum has peaks at 8.04 (1H, s), 7.30 (5H, s), 5.24 (2H, d),3.74 (3H, s), 3.66 (2H, s), 1.81 (3H, s) at 100 MHz in DMSO-d₆containing a drop of D₂ O.

The2-isopropyl-2-methoxycarbonyl-5-phenylacetamido-5,6-dehydrooxazine-4-oneupon hydrogenation in ethanol over 5% palladium on charcoal provided thedihydro derivative, melting point 178°-180°, having the followingstructure: ##STR26##

Its NMR spectrum shows the following peaks: 8.28 (1H, s), 7.38 (1H),7.23 (5H), 7.18 (1H), 3.76 (3H), 3.63 (2H), 2.24 (1H, m), 1.00 (3H, d, 7Hz), 0.94 (3H, d, 7 Hz).

The formation of2-isopropenyl-2-methoxycarbonyl-5-phenylacetamido-5,6-dehydrooxazine-4-onein the reaction with triethylamine requires the intervention of methyl2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-trans-4-bromo-2-butenoateand methyl2-(2'R-hydroxy-3'S-phenylacetamido-4'-oxo)azetidinyl-3-methyl-cis-4-bromo-2-butenoate.These compounds can be cyclized by the procedure of Example 8 to theepimeric2-bromomethyl-2-methyl-3R-methoxycarbonyl-6S-phenylacetamido-1-oxa-4-aza-5R-bicyclo-[3,2,0]heptan-7-ones.

EXAMPLE 12 Conversion of benzyl2-(2'R-phenylacetoxy-3'S-amino-4'-oxo)-azetidinyl-3-methyl-2-butenoatep-toluenesulfonate to2-isopropenyl-2-benzyloxycarbonyl-5-phenylacetamido-5,6-dehydrooxazine-4-oneand the epimeric2-bromomethyl-2-methyl-3R-benzyloxycarbonyl-6S-phenylacetamido-1-oxa-4-aza-5R-bicyclo[3,2,0]heptan-7-ones##STR27##

The p-toluenesulfonic acid salt (100 mg, 0.17 mMole) was suspended inCCl₄ (spectroscopic grade, 20 ml) containing N-bromosuccinimide (62 mg,0.35 mMole) and benzoyl peroxide (2mg). The mixture was heated to refluxwith mechanical stirring. After 2 min, the heat source was removed, andthe stirred mixture was irradiated with a 100 watt Photoflood No. 2 lampfor 8 min. Irradiation was then discontinued, and the reaction mixturewas evaporated to dryness to form the mixture XX and XXI whereR=R'=benzyl and A=p-tolyl. The residue was dissolved in methylenechloride (15 ml) and triethylamine (35 mg) was added to form the mixtureXXII and XXIII where R=R'=benzyl. This solution was stirred at 20° for1.5 hr and then evaporated. The residue was dissolved in methylenechloride, and this solution was washed with water, dried and evaporated.The 42 mg of material thus obtained was chromatographed on silica gel.Elution with graded mixtures of petroleum ether and ethyl acetateafforded 7 mg of material with the 1:1 mixture. This materialcrystallized when triturated with ether. Recrystallization frommethylene chloride-petroleum ether afforded2-isopropenyl-2-benzyloxycarbonyl-5-phenylacetamido-5,6-dehydrooxazine-4-one,m.p. 162°-163°. The NMR spectrum shows peaks at 8.33 (1H, s), 7.53 (10H,s), 5.50 (4H, br, s), 3.93 (2H, s), 1.98 (3H, s). The IR spectrum showscarbonyl absorptions at 1725, 1690 and 1642 cm⁻¹.

An alternative mode of cyclization of this mixture XXII and XXIII inwhich R=R'=benzyl, makes use of the procedure of Example 8 to form theepimeric2-bromomethyl-2-methyl-3R-benzyloxycarbonyl-6S-phenylacetamido-1-oxa-4-aza-5R-bicyclo[3,2,0]heptane-7-ones.

I claim:
 1. The CIS compound of the formula: ##STR28## wherein R standfor loweralkyl ##STR29## wherein R⁴ represents a member selected fromthe group consisting of hydrogen, amino, carbobenzoxyamino, phenyl,fluoro, chloro, bromo, iodo, and (lower)-alkoxy; X represents a memberselected from the group consisting of oxygen and sulfur; R⁵ and R⁶ eachrepresent a member selected from the group consisting of hydrogen,phenyl, benzyl, phenethyl and (lower)alkyl; R⁷ represents (lower)alkyl;R⁸ and R⁹ each represent a member selected from the group consisting of(lower)alkyl, (lower)alkylthio, benzylthio, cyclohexyl, cyclopentyl,cycloheptyl, benzyl, phenethyl, phenylpropyl, furyl, thienyl, naphthyland Ar--; R¹⁰ represents a member selected from the group consisting of(lower)alkylamino, di(lower)alkylamino, cycloalkylamino having from 3 to7 carbon atoms inclusive, allylamino, diallylamino,phenyl(lower)-alkylamino, morpholino, (lower)alkylmorpholino,di(lower)-alkylmorpholino, morpholino(lower)alkylamino, pyrrolidino,(lower) alkylpyrrlidino, di(lower)alkylpyrrolidino,N,N-hexamethyleneimino, piperidino, (lower)alkylpiperidino,di(lower)-alkylpiperidino, 1,2,5,6-tetrahydropyridino,N-(lower)-alkylpiperazino, N-phenylpiperazino,N-(lower)alkyl(lower)-alkylpiperazino,N-(lower)-alkyl-di(lower)alkylpiperazino, furfurylamino,tetrahydrofurfurylamino, N-(lower)alkyl-N-furfurylamino,N-alkyl-N-anilino and (lower)alkoxyanilino; Z¹, Z² and Z³ each representa member selected from the group consisting of (lower)alkyl and Ar--;R¹¹ represents a member selected from the group consisting of(lower)alkyl, (lower)-cycloalkyl, naphthyl, benzyl, phenethyl and##STR30## and Ar-- represents a monovalent radical having one of theformulae: ##STR31## ##STR32## wherein Ar is a monovalent radicalselected from ##STR33## wherein R₁, R₂ and R₃ are each a member selectedfrom hydrogen, chloro, bromo, iodo, trifluoromethyl, phenyl, loweralkyland loweralkoxy, but only one of said R₁, R₂ and R₃ may representphenyl;(R⁴ is hydrogen, amino, carbobenzoxyamino, phenyl, fluoro,chloro, bromo, iodo, and loweralkoxy; X is oxygen or sulfur; R⁵ and R⁶are hydrogen, phenyl, benzyl, phenethyl and loweralkyl; Z¹, Z² and Z³stand for loweralkyl or the Ar--group; R¹² is 2,2,2-trichloroethyl orbenzyl;R¹ is hydrogen, loweralkyl, benzyl, benzhydryl,loweralkoxybenzyl, or 2,2,2-trichloroethyl; and wherein R¹, R² and R³are each a member selected from the group consisting of hydrogen,chloro, bromo, iodo, trifluoromethyl, phenyl, (lower)alkyl and(llower)alkoxy, but only one of the groups R¹, R² and R³ may representphenyl.
 2. The compound of claim 1 which is methyl2-(2'R-phenylacetoxy-3'S-phenylcarboxamido-4'-oxo)azetidinyl-3-methyl-2-butenoate.